Genetically Determined Plasma Hepatocyte Growth Factor Levels Are Associated With the Risk and Prognosis of Ischemic Stroke.

BACKGROUND: Observational studies suggest that hepatocyte growth factor (HGF) is associated with the risk and prognosis of ischemic stroke, but the causality of these associations remains unclear. Therefore, we conducted Mendelian randomization (MR) analyses to explore the associations of genetically determined plasma HGF levels with the risk and prognosis of ischemic stroke. METHODS: A total of 13 single-nucleotide polymorphisms associated with plasma HGF were selected as genetic instruments based on the data from a genome-wide association study with 21 758 European participants. Summary data about the risk of ischemic stroke were obtained from the MEGASTROKE (Multiancestry Genome-Wide Association Study of Stroke) Consortium with 34 217 ischemic stroke cases and 406 111 controls of European ancestry, and summary data about the prognosis of ischemic stroke were obtained from the GISCOME study (Genetics of Ischaemic Stroke Functional Outcome) with 6165 European patients with ischemic stroke. We conducted an inverse-variance weighted Mendelian randomization analysis followed by a series of sensitivity analyses to evaluate the associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke. RESULTS: The primary analyses showed that genetically determined high HGF was associated with an increased risk of ischemic stroke (odds ratio per SD increase, 1.11 [95% CI, 1.04-1.19]; P=1.10×10-3) and poor prognosis of ischemic stroke (odds ratio per SD increase, 2.43 [95% CI, 1.76-3.52]; P=6.35×10-8). In the secondary analysis, genetically determined plasma HGF was associated with a high risk of large atherosclerotic stroke (odds ratio per SD increase, 1.39 [95% CI, 1.18-1.63]; P=5.08×10-5) but not small vessel stroke and cardioembolic stroke. Mendelian randomization-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different Mendelian randomization methods further confirmed these findings. CONCLUSIONS: We found positive associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke, suggesting that HGF might be implicated in the occurrence and development of ischemic stroke.

The identification of novel schizophrenia-related metabolites using untargeted lipidomics.

Human lipidome still remains largely unexplored among Chinese schizophrenia patients. We aimed to identify novel lipid molecules associated with schizophrenia and cognition among schizophrenia patients. The current study included 96 male schizophrenia patients and 96 gender-matched healthy controls. Untargeted lipidomics profiling was conducted among all participants. Logistic regression models were used to assess metabolite associations with schizophrenia. We further assessed the incremental predictive value of identified metabolites beyond conventional risk factors on schizophrenia status. In addition, identified metabolites were tested for association with cognitive function among schizophrenia patients using linear regression models. A total of 34 metabolites were associated with schizophrenia. Addition of these identified metabolites to age, body mass index, smoking, and education significantly increased the risk reclassification of schizophrenia. Among the schizophrenia-related metabolites, 10 were further associated with cognition in schizophrenia patients, including four metabolites associated with immediate memory, two metabolites associated with delayed memory, three metabolites associated with visuospatial, four metabolites associated with language, one metabolite associated with attention, and two metabolites associated with the total score. Our findings provide novel insights into the biological mechanisms of schizophrenia, suggesting that lipid metabolites may serve as potential diagnostic or therapeutic targets of schizophrenia.

The bidirectional association between frailty index and cardiovascular disease: A Mendelian randomization study.

BACKGROUND AND AIM: Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05-1.08]), MI (OR per 1-SD increase: 1.74 [1.21-2.51]), HF (OR per 1-SD increase: 1.28 [1.10-1.48]), and AF (OR per 1-SD increase: 1.20 [1.08-1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225-1.587]), MI (beta: 0.045 [0.023-0.067]), HF (beta: 0.105 [0.066-0.143]) and AF (beta: 0.021 [0.012-0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models. CONCLUSIONS: We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of intracerebral hemorrhage.

Previous observational studies have reported associations between brain imaging-derived phenotypes (IDPs) and intracerebral hemorrhage (ICH), but the causality between them remains uncertain. We aimed to investigate the potential causal relationship between IDPs and ICH by a two-sample Mendelian randomization (MR) study. We selected genetic instruments for 363 IDPs from a genome-wide association study (GWASs) based on the UK Biobank (n = 33,224). Summary-level data on ICH was derived from a European-descent GWAS with 1,545 cases and 1,481 controls. Inverse variance weighted MR method was applied in the main analysis to investigate the associations between IDPs and ICH. Reverse MR analyses were performed for significant IDPs to examine the reverse causation for the identified associations. Among the 363 IDPs, isotropic or free water volume fraction (ISOVF) in the anterior limb of the left internal capsule was identified to be associated with the risk of ICH (OR per 1-SD increase, 4.62 [95% CI, 2.18-9.81], P = 6.63 × 10-5). In addition, the reverse MR analysis indicated that ICH had no effect on ISOVF in the anterior limb of the left internal capsule (beta, 0.010 [95% CI, -0.010-0.030], P = 0.33). MR-Egger regression analysis showed no directional pleiotropy for the association between ISOVF and ICH, and sensitivity analyses with different MR models further confirmed these findings. ISOVF in the anterior limb of the left internal capsule might be a potential causal mediator of ICH, which may provide predictive guidance for the prevention of ICH. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Genetic analyses identify brain imaging-derived phenotypes associated with the risk of amyotrophic lateral sclerosis.

Brain imaging-derived phenotypes have been suggested to be associated with amyotrophic lateral sclerosis in observational studies, but whether these associations are causal remains unclear. We aimed to assess the potential bidirectional causal associations between imaging-derived phenotypes and amyotrophic lateral sclerosis using bidirectional 2-sample Mendelian randomization analyses. Summary statistics for 469 imaging-derived phenotypes (33,224 individuals) and amyotrophic lateral sclerosis (20,806 cases and 59,804 controls) were obtained from 2 large-scale genome-wide association studies of European ancestry. We used the inverse-variance weighted Mendelian randomization method in the main analysis to assess the bidirectional associations between imaging-derived phenotypes and amyotrophic lateral sclerosis, followed by several sensitivity analyses for robustness validation. In the forward Mendelian randomization analyses, we found that genetically determined high orientation dispersion index in the right cerebral peduncle was associated with the increased risk of amyotrophic lateral sclerosis (odds ratio = 1.30, 95% confidence interval = 1.16-1.45, P = 2.26 × 10-6). In addition, the reverse Mendelian randomization analysis indicated that amyotrophic lateral sclerosis had no effect on 469 imaging-derived phenotypes. Mendelian randomization-Egger regression analysis showed no directional pleiotropy for the association between high orientation dispersion index in the right cerebral peduncle and amyotrophic lateral sclerosis, and sensitivity analyses with different Mendelian randomization models further confirmed these findings. The present systematic bidirectional Mendelian randomization analysis showed that high orientation dispersion index in the right cerebral peduncle might be the potential causal mediator of amyotrophic lateral sclerosis, which may provide predictive guidance for the prevention of amyotrophic lateral sclerosis. Further studies are warranted to replicate our findings and clarify the underlying mechanisms.

Plasma Amino Acid Neurotransmitters and Ischemic Stroke Prognosis: A Multicenter Prospective Study.

BACKGROUND: Plasma amino acid neurotransmitter dysregulation is suggested to be implicated in the development of ischemic stroke, but its prognostic value for ischemic stroke remains controversial. OBJECTIVE: We aimed to prospectively investigate the associations between plasma amino acid neurotransmitters levels and adverse outcomes after ischemic stroke in a large-scale multicenter cohort study. METHODS: We measured 4 plasma amino acid neurotransmitters (glutamic acid, aspartic acid, gamma-aminobutyric acid, and glycine) among 3486 patients with ischemic stroke from 26 hospitals across China. The primary outcome is the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 mo after ischemic stroke. RESULTS: After multivariate adjustment, the odds ratios of death or major disability for the highest versus the lowest quartile were 2.04 (95% confidence interval [CI]: 1.60,2.59; P-trend < 0.001) for glutamic acid, 2.03 (95% CI: 1.59, 2.59; P-trend < 0.001) for aspartic acid, 1.35 (95% CI: 1.06, 1.71; P-trend = 0.016) for gamma-aminobutyric acid, and 0.54 (95% CI: 0.42, 0.69; P-trend < 0.001) for glycine. Each standard deviation increment of log-transformed glutamic acid, aspartic acid, gamma-aminobutyric acid, and glycine was associated with a 34%, 34%, and 9% increased risk, and a 23% decreased risk of death or major disability, respectively (all P < 0.05), in a linear fashion as indicated by spline regression analyses (all P for linearity < 0.05). Addition of the 4 plasma amino acid neurotransmitters to conventional risk factors significantly improved the risk reclassification, as evidenced by integrated discrimination improvement and net reclassification improvement (all P < 0.05). CONCLUSIONS: Increased glutamic acid, aspartic acid, and gamma-aminobutyric acid and decreased glycine in plasma are associated with adverse outcomes after ischemic stroke, suggesting that plasma amino acid neurotransmitters may be potential intervention targets for improving prognosis of ischemic stroke. The CATIS trial was registered at clinicaltrials.gov (registration number: NCT01840072; URL: ===https://clinicaltrials.gov/ct2/show/NCT01840072?cond=NCT01840072&draw=2&rank=1).

Mendelian randomization analysis implicates bidirectional associations between brain imaging-derived phenotypes and ischemic stroke.

Brian imaging-derived phenotypes (IDPs) have been suggested to be associated with ischemic stroke, but the causality between them remains unclear. In this bidirectional two-sample Mendelian randomization (MR) study, we explored the potential causal relationship between 461 imaging-derived phenotypes (n = 33,224, UK Biobank) and ischemic stroke (n = 34,217 cases/406,111 controls, Multiancestry Genome-Wide Association Study of Stroke). Forward MR analyses identified five IDPs associated with ischemic stroke, including mean diffusivity (MD) in the right superior fronto-occipital fasciculus (1.22 [95% CI, 1.11-1.34]), MD in the left superior fronto-occipital fasciculus (1.30 [1.17-1.44]), MD in the anterior limb of the right internal capsule (1.36 [1.22-1.51]), MD in the right anterior thalamic radiation (1.17 [1.09-1.26]), and MD in the right superior thalamic radiation (1.23 [1.11-1.35]). In the reverse MR analyses, ischemic stroke was identified to be associated with three IDPs, including high isotropic or free water volume fraction in the body of corpus callosum (beta, 0.189 [95% confidence interval, 0.107-0.271]), orientation dispersion index in the pontine crossing tract (0.175 [0.093-0.257]), and volume of the third ventricle (0.219 [0.138-0.301]). This bidirectional two-sample MR study suggested five predictors and three diagnostic markers for ischemic stroke at the brain-imaging level. Further studies are warranted to replicate our findings and clarify underlying mechanisms.

Causal Effects of YKL-40 on Ischemic Stroke and Its Subtypes: A 2-Sample Mendelian Randomization Study.

Background Chitinase-3 like protein 1 (CHI3L1, YKL-40) was reported to be implicated in the development of ischemic stroke, but whether the association between them was causal remained unclear. We conducted a 2-sample Mendelian randomization study to explore the associations of genetically determined plasma YKL-40 with ischemic stroke and its subtypes (large artery stroke, small vessel stroke, and cardioembolic stroke). Methods and Results Based on genome-wide association study data of 3394 European-descent individuals, we selected 13 single-nucleotide polymorphisms associated with plasma YKL-40 as genetic instruments. Summary data about ischemic stroke and its subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium, involving 34 217 ischemic stroke cases and 406 111 controls of European ancestry. We used the inverse-variance weighted method followed by a series of sensitivity analyses to assess the causal associations of plasma YKL-40 with ischemic stroke and its subtypes. The primary analysis showed that genetically determined high YKL-40 levels were associated with increased risks of large artery stroke (odds ratio [OR], 1.08 [95% CI, 1.04-1.12]; P=1.73×10-4) and small vessel stroke (OR, 1.05 [95% CI, 1.01-1.09]; P=7.96×10-3) but not with ischemic stroke or cardioembolic stroke. Sensitivity analyses further confirmed these associations, and Mendelian randomization-Egger indicated no evidence of genetic pleiotropy. In addition, supplementary analysis based on the summary data from the Olink proximity extension assay cardiovascular I (Olink CVD-I) panel showed that high YKL-40 levels were positively associated with the risks of large artery stroke (OR, 1.15 [95% CI, 1.08-1.22]; P=4.16×10-6) but not with small vessel stroke. Conclusions Genetically determined high plasma YKL-40 levels were causal associated with increased risks of large artery stroke.

Analysis of Zinc and Stromal Immunity in Disuse Osteoporosis: Mendelian Randomization and Transcriptomic Analysis.

OBJECTIVE: Disuse osteoporosis is known to be primarily caused by a lack of exercise. However, the causal relationships between zinc and immunity and disuse osteoporosis remain unknown. This study investigated these relationships and their potential mechanisms. METHODS: This study was an integrative study combining genome-wide association studies and transcriptomics. Two-sample Mendelian randomization analysis (MR) was used to analyze the causal relationships between exposures (zinc, immunity, physical activity) and the outcome (osteoporosis) with the aid of single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Four models, MR-Egger, inverse variance weighted, weighted median and MR-Pleiotrophy RESidual Sum and Outlier (MRPRESSO), were used to calculate odds ratio values. Sensitivity and heterogeneity analyses were also performed using MRPRESSO and MR-Egger methods. The mRNA transcriptomic analysis was subsequently conducted. Zinc metabolism scores were acquired through single-sample Gene Set Enrichment Analysis algorithms. Stromal scores were obtained using the R Package "estimate" algorithms. Important Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathways were also derived through gene set variation analysis. Cytoscape software helped construct the transcription factor (TF)-mRNA-microRNA (miRNA) network. Virtual screening and molecular docking were performed. Polymerase chain reaction validation was also carried out in vivo. RESULTS: Causal relationships were demonstrated between zinc and exercise (95% confidence interval [CI] = 1.30-2.95, p = 0.001), exercise and immunity (95% CI = 0.36-0.80, p = 0.002), exercise and osteoporosis (95% CI = 0.97-0.99, p = 0.0007), and immunity disorder and osteoporosis (95% CI = 1.30-2.03, p = 0.00002). One hundred and seventy-nine mRNAs in important modules were screened. Combining the differential expressional genes (DEGs) and the Boruta selection, six DEGs were screened (AHNAK, CSF2, ADAMTS12, SRA1, RUNX2, and SLC39A14). TF HOXC10 and miRNA hsa-miR-204 were predicted. Then, the TF-mRNA-miRNA network was successfully constructed. RUNX2 and SLC39A14 were identified as hub mRNAs in the TF-mRNA-miRNA network. Eventually, the novel small drug C6O4NH5 was designed according to the pharmacophore structure of SLC39A14. The docking energy for the novel drug was -5.83 kcal/mol. SLC39A14 and RUNX2 were downregulated (of statistical significance p-value < 0.05) in our animal experiment. CONCLUSION: This study revealed that zinc had a protective causal relationship with disuse osteoporosis by promoting exercise and immunity. SLC39A14 and RUNX2 mRNA participated in this zinc-related mechanism.

Inflammatory Bowel Disease and Risk of Global Cardiovascular Diseases and Type 2 Diabetes.

BACKGROUND: Inflammatory bowel disease (IBD) was associated with elevated risk of cardiometabolic diseases in observational studies. We aimed to evaluate the observational and genetic associations of Crohn's disease (CD) and ulcerative colitis (UC) with multiple cardiometabolic outcomes. METHODS: Our phenotypic and genetic association analyses included more than 400 000 participants who were free of major cardiovascular disease and diabetes at recruitment (2006-2010) and were followed up until December 2019 based on the UK Biobank. For the Mendelian randomization (MR) analyses, 415 and 273 single nucleotide polymorphisms associated with CD and UC, respectively, were selected as genetic instruments. Summary-level data on individual cardiometabolic outcomes were obtained from 4 different genome-wide association studies with a total of 2 248 842 participants. RESULTS: In the multivariable-adjusted observational analyses, CD was associated with higher risks of heart failure (hazard ratio [HR], 1.72; 95% confidence interval, 1.22-2.42) and type 2 diabetes (HR, 2.11; 95% confidence interval, 1.67-2.67) but not with myocardial infarction or ischemic stroke. UC was related to increased risks of all the assessed cardiometabolic diseases (HRs ranged from 1.29 for myocardial infarction to 1.76 for type 2 diabetes). Conversely, neither the genetic risk score for CD nor that for UC was associated with higher risk of developing cardiometabolic diseases. In 2-sample MR analyses, genetically determined CD and UC were not associated with any of the assessed cardiometabolic diseases (all P values >.05). CONCLUSIONS: Despite confirming the observational associations, our study does not support a causal association between IBD and elevated risk of cardiometabolic diseases.

Association Between Prekallikrein and Stroke: A Mendelian Randomization Study.

Background High plasma prekallikrein was reported to be associated with increased risks of stroke, but the causality for these associations remains unclear. We aimed to investigate the associations of genetically predicted plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, 3 ischemic stroke subtypes, and intracerebral hemorrhage (ICH) using a 2-sample Mendelian randomization approach. Methods and Results Seven independent prekallikrein-related single-nucleotide polymorphisms were identified as genetic instruments for prekallikrein based on a genome-wide association study with 1000 European individuals. The summary statistics for all-cause stroke, ischemic stroke, and ischemic stroke subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium with 40 585 cases and 406 111 controls of European ancestry. The summary statistics for ICH were obtained from the ISGC (International Stroke Genetics Consortium) with 1545 ICH cases and 1481 controls of European ancestry. In the main analysis, the inverse-variance weighted method was applied to estimate the associations of plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, ischemic stroke subtypes, and ICH. Genetically predicted high plasma prekallikrein levels were significantly associated with elevated risks of all-cause stroke (odds ratio [OR] per SD increase, 1.04 [95% CI, 1.02-1.06]; P=5.44×10-5), ischemic stroke (OR per SD increase, 1.05 [95% CI, 1.03-1.07]; P=1.42×10-5), cardioembolic stroke (OR per SD increase, 1.08 [95% CI, 1.03-1.12]; P=3.75×10-4), and small vessel stroke (OR per SD increase, 1.11 [95% CI, 1.06-1.17]; P=3.02×10-5). However, no significant associations were observed for genetically predicted prekallikrein concentrations with large artery stroke and ICH. Conclusions This Mendelian randomization study found that genetically predicted high plasma prekallikrein concentrations were associated with increased risks of all-cause stroke, ischemic stroke, cardioembolic stroke, and small vessel stroke, indicating that prekallikrein might have a critical role in the development of stroke.

circSNTB2 and CUL4A Induces Dysfunction of Nucleus Pulposus Cells by Competitively Binding miR-665.

Circular RNA (circRNA) plays important roles in lumbar degenerative diseases. This study aimed to investigate the role of circSNTB2 in regulating the development of lumbar disc herniation (LDH) in vitro and in vivo. The abnormally expressed circSNTB2 in intervertebral disc degeneration (IDD) through bioinformatics analysis was identified, and verified in nucleus pulposus (NP) tissues of patients with LDH. NP cells were treated with TNF-α to mimic the LDH microenvironment. RT-qPCR was applied to determine levels of mRNA and microRNA (miRNA) in clinical samples and cells. We performed CCK-8, EdU, TUNEL and flow cytometric apoptosis assays to evaluate the proliferation and apoptosis of NP cells. The predicted the miRNAs and downstream target genes were verified with the help of luciferase reporter gene and RNA pull-down experiments. Finally, we established an LDH rat model to further verify the role of circSNTB2 in vivo. circSNTB2 was significantly up-regulated in the NP tissues of LDH group and TNF-α -treated NP cells. miR-665 binds to circSNTB2 and cullin 4A (CUL4A) is the downstream target gene of miR-665. Knockdown of circSNTB2 promoted NP cells proliferation and inhibited apoptosis, which was reversed by down-regulation of miR-665. In addition, up-regulated CUL4A reversed the effects of over-expressed miR-665 on proliferation and apoptosis of NP cells. Meanwhile, results of in vivo experiments demonstrated that knocking down circSNTB2 alleviated LDH-induced thermo-mechanical pain and NP injury. In summary, circSNTB2 regulates the proliferation and apoptosis of NP by mediating miR-665 regulation of CUL4A, which provides a reliable idea for targeted therapy of LDH. Graphical abstract of how circSNTB2 promotes LDH progression. A schematic model of circSNTB2/miR-665/CUL4A signaling pathway in NP cells. CircSNTB2 competitively binds to miR-665, resulting in upregulation of CUL4A.

High Serum Brain-Derived Neurotrophic Factor Is Associated With Decreased Risks of Poor Prognosis After Ischemic Stroke.

BACKGROUND: BDNF (brain-derived neurotrophic factor) has been implicated in cardiovascular homeostasis and ischemic stroke pathogenesis. We aimed to prospectively investigate the associations between serum BDNF levels and the prognosis of ischemic stroke in a multicenter cohort study. METHODS: This prospective study follows the STROBE reporting guideline. Serum BDNF concentrations were measured in 3319 ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was the composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Multivariate logistic regression or Cox proportional hazards regression analysis was used to assess the associations between serum BDNF levels and adverse clinical outcomes. RESULTS: During the 3-month follow-up period, 827 (24.92%) patients experienced a primary outcome, including 734 major disabilities and 93 deaths. After adjusting for age, sex, and other important prognostic factors, elevated serum BDNF levels were associated with decreased risks of primary outcome (odds ratio, 0.73 [95% CI, 0.58-0.93]), major disability (odds ratio, 0.78 [95% CI, 0.62-0.99]), death (hazard ratio, 0.55 [95% CI, 0.32-0.97]), and the composite outcome of death and vascular events (hazard ratio, 0.61 [95% CI, 0.40-0.93]) when 2 extreme tertiles were compared. Multivariable-adjusted spline regression analyses showed a linear association between serum BDNF levels and the primary outcome (P value for linearity=0.005). The addition of BDNF to conventional risk factors slightly improved reclassification for the primary outcome (net reclassification improvement: 19.33%; P<0.001; integrated discrimination index: 0.24%; P=0.011). CONCLUSIONS: Elevated serum BDNF concentrations were independently associated with decreased risks of adverse outcomes after ischemic stroke, suggesting that serum BDNF may be a potential biomarker for prognosis after ischemic stroke. Further studies are warranted to investigate the potential therapeutic benefit of BDNF for ischemic stroke.

Associations of Rheumatoid Factor, Rheumatoid Arthritis, and Interleukin-6 Inhibitor with the Prognosis of Ischemic Stroke: a Prospective Multicenter Cohort Study and Mendelian Randomization Analysis.

Rheumatoid factor (RF), an established diagnostic biomarker for rheumatoid arthritis (RA), is associated with cardiovascular diseases, but its impact on clinical outcomes of ischemic stroke remains unclear. We aimed to investigate the observational associations between serum RF and prognosis of ischemic stroke, and further examined the genetic associations of RA and its therapeutic strategy, interleukin-6 (IL-6) inhibitor, with prognosis of ischemic stroke. We measured serum RF levels in 3474 Chinese ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Mendelian randomization (MR) analyses were performed to examine the associations of genetically predicted RA and IL-6 inhibition with prognosis of ischemic stroke. During 3 months of follow-up, 866 patients (25.43%) experienced death or major disability. After multivariate adjustment, RF-positive was significantly associated with a high risk of primary outcome (OR, 1.47; 95% CI, 1.08-2.00; P =0.016) compared with RF-negative. The two-sample MR analyses suggested that genetically predicted RA was associated with an increased risk of primary outcome (OR, 1.09; 95% CI, 1.01-1.18; P=0.021), while genetically predicted IL-6 inhibition was associated with a decreased risk of primary outcome (OR, 0.88; 95% CI, 0.77-0.99; P=0.041). We found that positive RF was associated with increased risks of adverse outcomes after atherosclerotic ischemic stroke, and genetically predicted RA and IL-6 inhibition increased and decreased the risks of adverse outcomes after ischemic stroke, respectively.

Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study.

BACKGROUND: Experimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes. METHODS: A total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes. RESULTS: Genetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01-1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02-1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03-1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings. CONCLUSIONS: We found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.

Association between human blood metabolome and the risk of breast cancer.

BACKGROUND: Breast cancer is the most common cancer among women with limited treatment options. To identify promising drug targets for breast cancer, we conducted a systematical Mendelian randomization (MR) study to screen blood metabolome for potential causal mediators of breast cancer and further predict target-mediated side effects. METHODS: We selected 112 unique blood metabolites from 3 large-scale European ancestry-based genome-wide association studies (GWASs) with a total of 147,827 participants. Breast cancer data were obtained from a GWAS in the Breast Cancer Association Consortium (BCAC), involving 122,977 cases and 105,974 controls of European ancestry. We conducted MR analyses to systematically assess the associations of blood metabolites with breast cancer, and a phenome-wide MR analysis was further applied to ascertain the potential on-target side effects of metabolite interventions. RESULTS: Two blood metabolites were identified as the potential causal mediators for breast cancer, including high-density lipoprotein cholesterol (HDL-C) (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.06-1.12; P = 9.67 × 10-10) and acetate (OR, 1.24; 95% CI, 1.13-1.37; P = 1.35 × 10-5). In the phenome-wide MR analysis, lowering HDL-C might have deleterious effects on the risk of the circulatory system and foreign body injury, while lowering acetate had deleterious effects on mental disorders disease. CONCLUSIONS: The present systematic MR analysis revealed that HDL-C and acetate may be the causal mediators in the risk of developing breast cancer. Side-effect profiles were characterized to help inform drug target prioritization for breast cancer prevention. HDL-C and acetate might be promising drug targets for preventing breast cancer, but they should be applied under weighting advantages and disadvantages.

Identification of potential causal metabolites associated with atopic dermatitis.

Atopic dermatitis is a chronically recurrent dermatologic disease affected by complex pathophysiology with limited therapeutic options. To identify promising biomarkers for atopic dermatitis, we conducted a Mendelian randomization (MR) study to systematically screen blood metabolome for potential causal mediators of atopic dermatitis and further predict target-mediated side effects. We selected 128 unique blood metabolites from three European-descent metabolome genome-wide association studies (GWASs) with a total of 147 827 participants. Atopic dermatitis dataset originated from a large-scale GWAS including 10 788 cases and 30 047 controls of European ancestry. MR analyses were performed to estimate the associations of blood metabolites with atopic dermatitis. We then applied a phenome-wide MR analysis to ascertain potential on-target side effects of metabolite intervention. Three metabolites were identified as potential causal mediators for atopic dermatitis, including docosahexaenoic acid (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.81-0.94; P = 3.45 × 10-4), arachidonate (OR, 0.30; 95% CI, 0.17-0.53; P = 4.09 × 10-5) and 1-arachidonoylglycerophosphoethanolamine (1-arachidonoyl-GPE) (OR, 0.25; 95% CI, 0.12-0.53; P = 2.58 × 10-4). In the phenome-wide MR analysis, docosahexaenoic acid and arachidonate were also identified to have beneficial or detrimental effects on multiple diseases beyond atopic dermatitis, respectively. No adverse side effects were found for 1-arachidonoyl-GPE. In this systematic MR study, docosahexaenoic acid, arachidonate and 1-arachidonoyl-GPE were identified as potential causal and beneficial mediators in the development of atopic dermatitis. Side-effect profiles were characterized to help inform drug target prioritization, and 1-arachidonoyl-GPE was a promising target for prevention and treatment of atopic dermatitis with no predicted adverse side effects.

Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders.

BACKGROUND AND HYPOTHESIS: To identify promising drug targets for psychiatric disorders, we applied Mendelian randomization (MR) design to systematically screen blood metabolome for potential mediators of psychiatric disorders and further predict target-mediated side effects. STUDY DESIGN: We selected 92 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with totally 147 827 participants. Summary statistics for bipolar disorder (BIP), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), schizophrenia (SCZ), panic disorder (PD), autistic spectrum disorder (ASD), and anorexia nervosa (AN) originated from the Psychiatric Genomics Consortium, involving 1 143 340 participants. Mendelian randomization (MR) analyses were conducted to estimate associations of blood metabolites with psychiatric disorders. Phenome-wide MR analysis was further performed to predict side effects mediated by metabolite-targeted interventions. RESULTS: Eight metabolites were identified associated with psychiatric disorders, including five established mediators: N-acetylornithine (BIP: OR, 0.72 [95% CI, 0.66-0.79]; SCZ: OR, 0.74 [0.64-0.84]), glycine (BIP: OR, 0.62 [0.50-0.77]), docosahexaenoic acid (MDD: OR, 0.96 [0.94-0.97]), 3-Hydroxybutyrate (MDD: OR, 1.14 [1.08-1.21]), butyrylcarnitine (SCZ: OR, 1.22 [1.12-1.32]); and three novel mediators: 1-arachidonoylglycerophosphocholine (1-arachidonoyl-GPC)(BIP: OR, 0.31 [0.23-0.41]), glycoproteins (BIP: OR, 0.94 [0.92-0.97]), sphingomyelins (AN: OR, 1.12 [1.06-1.19]). Phenome-wide MR analysis showed that all identified metabolites except for N-acetylornithine and 3-Hydroxybutyrate had additional effects on nonpsychiatric diseases, while glycine, 3-Hydroxybutyrate, N-acetylornithine, and butyrylcarnitine had no adverse side effects. CONCLUSIONS: This MR study identified five established and three novel mediators for psychiatric disorders. N-acetylornithine, glycine, 3-Hydroxybutyrate, and butyrylcarnitine might be promising targets against psychiatric disorders with no predicted adverse side effects.

Osteoprotegerin and Ischemic Stroke Prognosis: A Prospective Multicenter Study and Mendelian Randomization Analysis.

BACKGROUND: Osteoprotegerin was implicated in vascular injury and inflammatory responses, but its prognostic value in ischemic stroke remained unclear. We aimed to prospectively investigate the association between plasma osteoprotegerin and ischemic stroke prognosis combined with a Mendelian randomization analysis. METHODS: Our prospective study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline. We measured baseline plasma osteoprotegerin levels for 3490 ischemic stroke patients recruited between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was a composite outcome of death and major disability at 3 months after ischemic stroke. RESULTS: After adjustment for age, sex, admission National Institutes of Health Stroke Scale score, and other important covariates, elevated osteoprotegerin levels were associated with increased risks of primary outcome (odds ratio, 1.40 [95% CI, 1.05-1.88]), death (hazard ratio, 2.05 [95% CI, 1.04-4.08]), and composite outcome of death and vascular events (hazard ratio, 2.00 [95% CI, 1.15-3.48]) when 2 extreme quartiles were compared. Each 1-SD higher log-osteoprotegerin was associated with a 18% (95% CI, 6%-32%) increased risk of primary outcome, 69% (95% CI, 31%-118%) increased risk of death, and 53% (95% CI, 24%-89%) increased risk of composite outcome of death and vascular events, respectively. Multiple-adjusted spline regression model showed a linear association of osteoprotegerin with primary outcome (P for linearity <0.001). Adding osteoprotegerin to conventional risk factors did not significantly improve discriminatory power (C statistics, 0.817 versus 0.818; P=0.232) but did slightly improve the risk reclassification of primary outcome (net reclassification improvement: 13.68%, P<0.001; integrated discrimination improvement: 0.23%, P=0.039). In Mendelian randomization analysis, genetically determined high plasma osteoprotegerin was associated with increased risk of primary outcome (odds ratio, 5.74 [95% CI, 1.12-29.44]; P=0.036). CONCLUSIONS: Elevated plasma osteoprotegerin was associated with poor prognosis of ischemic stroke, and genetically determined high plasma osteoprotegerin was associated with an increased risk of primary outcome in Mendelian randomization analysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.

Association between myeloperoxidase and the risks of ischemic stroke, heart failure, and atrial fibrillation: A Mendelian randomization study.

BACKGROUND AND AIMS: The causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Seventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02-1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03-1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02-1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings. CONCLUSION: High plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease.